Protein & Cell

, Volume 1, Issue 12, pp 1106–1117 | Cite as

Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

Research Article

Abstract

Hepatitis B virus (HBV) is regarded as a stealth virus, invading and replicating efficiently in human liver undetected by host innate antiviral immunity. Here, we show that type I interferon (IFN) induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells. This effect may be partially due to HBV X protein (HBx), which impairs IFNβ promoter activation by both Sendai virus (SeV) and components implicated in signaling by viral sensors. As a deubiquitinating enzyme (DUB), HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1 (TBK1). It binds and deconjugates retinoic acid-inducible gene I (RIG I) and TNF receptor-associated factor 3 (TRAF3), causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase. In addition to RIG I and TRAF3, HBx also interacts with CARDIF, TRIF, NEMO, TBK1, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon (IKKi) and interferon regulatory factor 3 (IRF3). Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.

Keywords

hepatitis B virus (HBV) HBV X protein (HBx) deubiquitination type I interferon 

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References

  1. Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783–801.CrossRefPubMedGoogle Scholar
  2. Bhoj, V.G., and Chen, Z.J. (2009). Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437.CrossRefPubMedGoogle Scholar
  3. Bouchard, M.J., and Schneider, R.J. (2004). The enigmatic X gene of hepatitis B virus. J Virol 78, 12725–12734.PubMedCentralCrossRefPubMedGoogle Scholar
  4. Bowie, A.G., and Unterholzner, L. (2008). Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8, 911–922.CrossRefPubMedGoogle Scholar
  5. Christen, V., Duong, F., Bernsmeier, C., Sun, D., Nassal, M., and Heim, M.H. (2007). Inhibition of alpha interferon signaling by hepatitis B virus. J Virol 81, 159–165.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Dienstag, J.L. (2008). Hepatitis B virus infection. N Engl J Med 359, 1486–1500.CrossRefPubMedGoogle Scholar
  7. Dunn, C., Peppa, D., Khanna, P., Nebbia, G., Jones, M., Brendish, N., Lascar, R.M., Brown, D., Gilson, R.J., Tedder, R.J., et al. (2009). Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137, 1289–1300.CrossRefPubMedGoogle Scholar
  8. Fernández, M., Quiroga, J.A., and Carreño, V. (2003). Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins. J Gen Virol 84, 2073–2082.CrossRefPubMedGoogle Scholar
  9. Fisicaro, P., Valdatta, C., Boni, C., Massari, M., Mori, C., Zerbini, A., Orlandini, A., Sacchelli, L., Missale, G., and Ferrari, C. (2009). Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 58, 974–982.CrossRefPubMedGoogle Scholar
  10. Friedman, C.S., O’Donnell, M.A., Legarda-Addison, D., Ng, A., Cárdenas, W.B., Yount, J.S., Moran, T.M., Basler, C.F., Komuro, A., Horvath, C.M., et al. (2008). The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep 9, 930–936.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Gack, M.U., Shin, Y.C., Joo, C.H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S., et al. (2007). TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920.CrossRefPubMedGoogle Scholar
  12. Gao, D., Yang, Y.K., Wang, R.P., Zhou, X., Diao, F.C., Li, M.D., Zhai, Z.H., Jiang, Z.F., and Chen, D.Y. (2009). REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I. PLoS One 4, e5760.PubMedCentralCrossRefPubMedGoogle Scholar
  13. Guo, B., and Cheng, G. (2007). Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK. J Biol Chem 282, 11817–11826.CrossRefPubMedGoogle Scholar
  14. Guy, C.S., Mulrooney-Cousins, P.M., Churchill, N.D., and Michalak, T. I. (2008). Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol 82, 8579–8591.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Hochstrasser, M. (2009). Origin and function of ubiquitin-like proteins. Nature 458, 422–429.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Honda, K., Takaoka, A., and Taniguchi, T. (2006). Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25, 349–360.CrossRefPubMedGoogle Scholar
  17. Kawagoe, T., Takeuchi, O., Takabatake, Y., Kato, H., Isaka, Y., Tsujimura, T., and Akira, S. (2009). TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol 10, 965–972.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., et al. (2004). Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5, 1061–1068.CrossRefPubMedGoogle Scholar
  19. Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O’Rourke, K.M., Eby, M., Pietras, E., Cheng, G., Bazan, J.F., et al. (2007). DUBA: a deubiquitinase that regulates type I interferon production. Science 318, 1628–1632.CrossRefPubMedGoogle Scholar
  20. Li, K., Chen, Z., Kato, N., Gale, M. Jr, and Lemon, S.M. (2005). Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. J Biol Chem 280, 16739–16747.CrossRefPubMedGoogle Scholar
  21. Lok, A.S., and McMahon, B.J. (2007). Chronic hepatitis B. Hepatology 45, 507–539.CrossRefPubMedGoogle Scholar
  22. McCartney, S.A., and Colonna, M. (2009). Viral sensors: diversity in pathogen recognition. Immunol Rev 227, 87–94.CrossRefPubMedGoogle Scholar
  23. Medzhitov, R. (2007). Recognition of microorganisms and activation of the immune response. Nature 449, 819–826.CrossRefPubMedGoogle Scholar
  24. Melegari, M., Scaglioni, P.P., and Wands, J.R. (1998). Cloning and characterization of a novel hepatitis B virus x binding protein that inhibits viral replication. J Virol 72, 1737–1743.PubMedCentralPubMedGoogle Scholar
  25. O’Neill, L.A. (2009). DNA makes RNA makes innate immunity. Cell 138, 428–430.CrossRefPubMedGoogle Scholar
  26. Oshiumi, H., Matsumoto, M., Hatakeyama, S., and Seya, T. (2009). Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. J Biol Chem 284, 807–817.CrossRefPubMedGoogle Scholar
  27. Pang, R., Lee, T.K., Poon, R.T., Fan, S.T., Wong, K.B., Kwong, Y.L., and Tse, E. (2007). Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology 132, 1088–1103.CrossRefPubMedGoogle Scholar
  28. Randall, R.E., and Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89, 1–47.CrossRefPubMedGoogle Scholar
  29. Randow, F., and Lehner, P.J. (2009). Viral avoidance and exploitation of the ubiquitin system. Nat Cell Biol 11, 527–534.CrossRefPubMedGoogle Scholar
  30. Reyes-Turcu, F.E., Ventii, K.H., and Wilkinson, K.D. (2009). Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78, 363–397.CrossRefPubMedGoogle Scholar
  31. Sabbah, A., Chang, T.H., Harnack, R., Frohlich, V., Tominaga, K., Dube, P.H., Xiang, Y., and Bose, S. (2009). Activation of innate immune antiviral responses by Nod2. Nat Immunol 10, 1073–1080.PubMedCentralCrossRefPubMedGoogle Scholar
  32. Saitoh, T., Tun-Kyi, A., Ryo, A., Yamamoto, M., Finn, G., Fujita, T., Akira, S., Yamamoto, N., Lu, K.P., and Yamaoka, S. (2006). Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat Immunol 7, 598–605.CrossRefPubMedGoogle Scholar
  33. Schroder, K., Muruve, D.A., and Tschopp, J. (2009). Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol 19, R262–R265.CrossRefPubMedGoogle Scholar
  34. Tang, H., Delgermaa, L., Huang, F., Oishi, N., Liu, L., He, F., Zhao, L., and Murakami, S. (2005). The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication. J Virol 79, 5548–5556.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Tenoever, B.R., Ng, S.L., Chua, M.A., McWhirter, S.M., GarcÍa-Sastre, A., and Maniatis, T. (2007). Multiple functions of the IKKrelated kinase IKKepsilon in interferon-mediated antiviral immunity. Science 315, 1274–1278.CrossRefPubMedGoogle Scholar
  36. Wang, C., Chen, T., Zhang, J., Yang, M., Li, N., Xu, X., and Cao, X. (2009). The E3 ubiquitin ligase Nrdp1’ preferentially’ promotes TLR-mediated production of type I interferon. Nat Immunol 10, 744–752.CrossRefPubMedGoogle Scholar
  37. Wang, H., and Ryu, W.S. (2010). Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog 6, e1000986.PubMedCentralCrossRefPubMedGoogle Scholar
  38. Wang, X., Li, Y., Mao, A., Li, C., Li, Y., and Tien, P. (2010). Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFNbeta induction by disrupting the VISA-associated complex. Cell Mol Immunol 7, 341–348.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Weber, S., Maass, F., Schuemann, M., Krause, E., Suske, G., and Bauer, U.M. (2009). PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling. Genes Dev 23, 118–132.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Webster, G.J., Reignat, S., Maini, M.K., Whalley, S.A., Ogg, G.S., King, A., Brown, D., Amlot, P.L., Williams, R., Vergani, D., et al. (2000). Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32, 1117–1124.CrossRefPubMedGoogle Scholar
  41. Wei, C., Ni, C., Song, T., Liu, Y., Yang, X., Zheng, Z., Jia, Y., Yuan, Y., Guan, K., Xu, Y., et al. (2010). The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J Immunol 185, 1158–1168.CrossRefPubMedGoogle Scholar
  42. Whitten, T.M., Quets, A.T., and Schloemer, R.H. (1991). Identification of the hepatitis B virus factor that inhibits expression of the beta interferon gene. J Virol 65, 4699–4704.PubMedCentralPubMedGoogle Scholar
  43. Wieland, S., Thimme, R., Purcell, R.H., and Chisari, F.V. (2004). Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 101, 6669–6674.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Wieland, S.F., and Chisari, F.V. (2005). Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 79, 9369–9380.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Wu, J., Meng, Z., Jiang, M., Pei, R., Trippler, M., Broering, R., Bucchi, A., Sowa, J.P., Dittmer, U., Yang, D., et al. (2009). Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology 49, 1132–1140.CrossRefPubMedGoogle Scholar
  46. Wu, M., Xu, Y., Lin, S., Zhang, X., Xiang, L., and Yuan, Z. (2007). Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1. J Gen Virol 88, 3260–3269.CrossRefPubMedGoogle Scholar
  47. Zeng, W., Sun, L., Jiang, X., Chen, X., Hou, F., Adhikari, A., Xu, M., and Chen, Z.J. (2010). Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141, 315–330.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Zeng, W., Xu, M., Liu, S., Sun, L., and Chen, Z.J. (2009). Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell 36, 315–325.PubMedCentralCrossRefPubMedGoogle Scholar
  49. Zhao, T., Yang, L., Sun, Q., Arguello, M., Ballard, D.W., Hiscott, J., and Lin, R. (2007). The NEMO adaptor bridges the nuclear factorkappaB and interferon regulatory factor signaling pathways. Nat Immunol 8, 592–600.CrossRefPubMedGoogle Scholar
  50. Zheng, D., Chen, G., Guo, B., Cheng, G., and Tang, H. (2008). PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production. Cell Res 18, 1105–1113.PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Key laboratory of Infection and Immunity of Chinese Academy of SciencesInstitute of BiophysicsBeijingChina
  2. 2.Graduate School of Chinese Academy of SciencesBeijingChina

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